Age-related changes to microbiome fuel vascular decline, new study shows

Changes in the gut microbiome as we age have an adverse impact on vascular health, according to a new study by researchers at the University of Colorado Boulder, which was published in the Journal of Physiology.

"This is the first study to show that changes in the gut microbiome with aging have an adverse impact on vascular health," said lead author Vienna Brunt, a postdoctoral researcher in the Department of Integrative Physiology.

The discovery opens up opportunities for potential interventions to prevent cardiovascular disease, said Vienna Brunt, PhD, lead author and a postdoctoral researcher in the Department of Integrative Physiology, in a statement released by the university.

For the study, researchers gave both young and old mice broad-spectrum antibiotics to kill off bacteria living in their gut. Then they assessed the health of their vascular endothelium, the inner lining of their blood vessels, and the stiffness of their large arteries.

They also measured blood levels of inflammatory compounds, tissue-damaging free-radicals, antioxidants and the blood-vessel-expanding compound nitric oxide in both groups, according to the study abstract.

After three to four weeks of the treatment, the young mice saw no change in vascular health. The old mice, however, saw vast improvements on all measures.

Suppressing the microbiome of the old mice led to vascular health restoring to that of young mice, said Doug Seals, PhD, senior author and director of the Integrative Physiology of Aging Laboratory.

 "This suggests there is something about those microorganisms that is causing vascular dysfunction,” he said.

To assess this, the researchers took fecal samples from another set of mice and had them genetically sequenced, comparing the gut bacteria living in the old mice with that in the young. In general, researchers found in the old mice, there was an increased prevalence of microbes that are pro-inflammatory and have been previously associated with diseases.

For instance, the old mice hosted significantly more Proteobacteria, a phyla that includes Salmonella and other pathogens, and pro-inflammatory Desulfovibrio, researchers said.

To drill down further, the researchers measured blood levels of metabolites, small molecules produced by the gut microorganisms and absorbed into the bloodstream, in old and young mice.

Old mice had three times as much trimethylamine N-oxide (TMAO), a metabolite shown in previous studies to be linked to increased risk of atherosclerosis, heart attack, and stroke.

Risk for cardiovascular disease begins to increase in individuals as early as 45 years old, according to the American Heart Association. By 60-79 years old, 70 percent of people in the United States have some form of cardiovascular disease, and by age 80, one in five are free of it. The exact cause of healthy arteries stiffening and losing function with age has remained somewhat of a medical mystery.

"We have long known that oxidative stress and inflammation are involved in making arteries unhealthy over time, but we didn't know why arteries begin to get inflamed and stressed,” Seals said. “Something is triggering this.”

Researchers now suspect that, with age, the gut microbiota begins producing toxic molecules, including TMAO, which get into the blood stream, cause inflammation and oxidative stress, and damage tissue.

Seals and Brunt stress that they are not suggesting people use antibiotics to prevent cardiovascular disease and maintain heart health. But they do believe that diets high in probiotic-rich cultured foods such as yogurt, kefir, and kimchi, and prebiotic fiber could play a role in preventing heart disease by promoting a healthy gut microbiome.

They're also studying a compound called dimethyl butanol, found in some olive oils, vinegars, and red wines, which blocks the bacterial enzyme required to produce TMAO. Ultimately, researchers say it could be developed into a dietary supplement.